DE862011C - Process for the manufacture of pyridine caps - Google Patents

Description

Process for the preparation of pyridine derivatives The present The invention relates to the production of pyriline derivatives which contain one or more, optionally contain further substituted CN radicals as core substituents, namely of cyanopyridines, pyridinecarboxamides and cyanpyridincarboxamides.

So far, 3-cyanopyridine has been made from pyriyyn-3-sulfonic acid in an economical manner produced, which is obtained from pyridine by sulfonation.

Pyriline-2-carboxamide (picolinic acid amide) was previously made from picolinic acid esters produced by reaction with ammonia. For this purpose picolinic acid is used first obtained by oxidation of a-picoline and then with low molecular weight Esterified alcohols, a relatively cumbersome way. It is also known to prepare the 6-cyanopyridine-3-carboxamide from pyridine, but in this synthesis of the product, several steps are required, as is the case with the previously known one Production of 6-substituted 2-cyanopyridines.

According to the present invention, the production of u. a. 3-cyanopyridine from an easily accessible and relatively cheap source, namely from alkylpyri3ines, which .without difficulty by the action of Ammonia can be synthesized on acetaldehyde, without pyridine as a starting product and this only via the intermediate stage of sulfonic acid derivatives to be processed.

Furthermore, according to the above invention, pyridine-α-carboxamides are used from easily accessible a-substituted Pyridines and alkyl pyridines produced while avoiding the oxidation, esterification and amide formation process. Furthermore, cyanopyridinecarboxamides, in particular the 6-cyanopyridine-3-carboxamide, produced without the previously necessary intermediate stages will.

The C N-substituted pyridine derivatives prepared according to the invention can in part already be identified as such, i.e. H. in unchanged condition, in different Use wisely, partly they can be easily converted into connections, - which are used in the synthesis of various pharmaceuticals and other products Find.

The method according to the invention exists in its most general form in that vapor mixtures of an alkyl pyridine, ammonia and oxygen-containing Gas with a catalyst consisting of an oxide or a salt of elements of the 5th, 6th or B. group of the periodic table exists or contains one, at an elevated temperature, which depends on the temperature used in the individual case Alkyl derivatives and / or the catalysts used directs, in contact to be brought.

As a starting material for carrying out the method according to the invention very generally speaking, alkylpyridines can be considered, which are any May have number of alkyl substituents of any chain length. Under Particular mention may be made of the suitable materials, the Picohne, i. H. the 2-, the 3- and 4-methylpyridine, the lutidines, i. H. the 2, 4-, the 2, 5-, the 2, 3-, the 2, 6- and 3, -4-dimethylpyridine, the collidines, d. H. the 2, 4, 5-, the 2, 3, 4-, the 2, 4, 6-, the 2, 3, 6- and the 2, 3, 5-trimethylpyridine, the 2-, the 3- and 4-ethylpyridine, ethylpyridine, such as 2-methyl-5-ethylpyridine, also alkylpyridines with longer side chains, such as propyl, butyl, hexyl, heptyl, Octylpyridines, and even higher molecular weight alkylpyridines.

Particularly suitable starting materials are the by-products alkylpyridines, which usually have no more than 4 carbon atoms in one seated on the pyridine ring Have alkyl substituents.

The oxides and salts of the elements of the 5th, 6. and B. group of the periodic table individually or as a mixture, either two or several different oxides or two or more different salts or one Mixture of one or more oxides with one or more salts are used: The activity of these catalysts can be increased by the presence of supports, accelerators and retarders are regulated to partial oxidation and nitrogen substitution to complete. In any case, the catalyst used or the catalyst mixture must naturally possess the property of a complete oxidation of the alkylpyridine to avoid.

According to a particular embodiment of the invention, an oxide an element of the specified groups in combination with an aluminum oxide carrier applied. The aluminum oxide serves to accelerate the reaction with improvement the yield of CN-substituted pyridine derivatives. The catalysts can, off Their salt solutions can be obtained by precipitation, whereupon the precipitation is either dries and granulates to prepare the metal salt catalyst, or in one Kiln calcined and granulated to obtain the oxide catalyst. In everyone In this case, the granules have a = o-mesh screen fineness. The precipitate can optionally be used mixed with a suitable binder and in the form of pills, tablets, beads or poles are prepared. Another method of making the catalyst consists in the fact that the catalytic material on small particles, advantageous pea size, pumice stone, clay, silica, or other inert materials precipitates or is sprayed on it.

Which end products are created depends on the respective applied starting materials, catalysts and other reaction conditions, such as, in particular, temperatures, reaction time, applied gas velocities. These conditions must be met beforehand with a view to the desired end product on the basis of preliminary tests, taking into account the general and special below Part of the description given guidelines and information are determined. In detail have the following starting materials for the production of the pyridine derivative groups mentioned proved to be advantageous: a) For the preparation of cyanopyridine from 3- or 4-alkylpyridine the picoline, d. H. 3- and 4-methylpyridine, 3- and 4-ethylpyridine, the lutidines, d. H. the 2, 5-dimethylpyridine, but also the 2, 4-, the 2, 3- and the 3, 4-dimethylpyridine, methylethylpyridine, such as the 2-methyl-5-ethylpyridine, also alkyl pyridines with longer side chains.

b) For the preparation of 6-substituted 2-cyanopyridines the 2, 6-dialkylpyridines of any chain length. Among those eligible for this Materials should be mentioned in particular various dialkylpyridines, e.g. B. the lutidines, d. H. the 2,6-dimethylpyridine, also the dialkylpyridines with a longer side chain.

c) For the preparation of pyridine-2-carboxamides, the 2-alkylpyridines of any chain length; are among the materials particularly suitable for this mentions 2-methylpyridine, 2-ethylpyridine, also 2-alkylpyridine _ finite longer side chain.

d) For the production of 6-cyanopyridine-3-carboxamides corresponding lutidine, d. H. the 3, 6-dimethylpyridine, methylethylpyridine, z. B. 6-methyl-3-ethylpyridine, also dialkylpyridines with a longer side chain.

According to a preferred embodiment of the invention, the alkyl pyridine by bubbling a measured amount of air through it at a previously evaporated at a certain temperature, the vapors obtained are then combined with ammonia gas mixed to produce a homogeneous gas mixture, which is then preheated and is passed over a catalyst, which is in a metal tube, preferably from stainless steel equipped with a heating element is attached. At Instead of using air, you can also mix it with carbon dioxide or oxygen another inert gas, e.g. B. steam, apply. Preheating the vapors can be done in any way, e.g. B. by heating the initially produced Mixing or heating one or two components of the vapors before formation of the mixture.

The reaction in the presence of the catalysts is preferably at Atmospheric pressure or at superatmospheric pressure which is sufficient to provide a suitable To allow control of the flow of the reactants over the catalyst carried out. If necessary, sub-atmospheric pressure can also be used, namely if you want to regulate the steam flow precisely. In this case one sucks at the exit end of the Apparatus on.

The yield of the desired CN-substituted pyridine derivatives can be increased considerably by using an excess of ammonia and air or oxygen. Although an excess of these vapors or gases increases the yields, high yields are only obtained when very large excess amounts are used. There are z. For example, about 30 moles of oxygen and about 10 moles of ammonia for each mole of alkyl pyridine usually give very good results. The amount of excess which gives optimal results depends on the type of alkylpyridine treated, the temperature used and the type of catalyst used. Generally speaking, the temperature of the reaction should be tailored to achieve the desired product. It is usually between 250 and 50 degrees. In the preparation of 3- or q-cyanopyridine and 6-cyanopyridine-3-carboxamide, the best results are generally obtained between 30 ° and 370 °, in the preparation of pyridine-2-carboxamides between 25 ° and 32 °, in particular at about 30o °, in the production of 6-substituted 2-cyanopyridines at 30o to 37o ', preferably at 30o to 32o °. Temperatures lower than the specified lower limit usually do not cause the reaction to proceed, and temperatures higher than the specified upper limit usually cause decomposition or dealkylation of the pyridine. In the continuous process, the time at which the reactants come into contact with the catalyst must be regulated if high yields of the desired compound are to be obtained. If the contact time is too short, the yields would be undesirably low due to the lack of sufficient reaction. If the time is too long, the result would be the same because the desired products would be destroyed by incineration. The optimal contact time and other conditions for each individual raw material can easily be determined by means of a preliminary test.

Usually a throughput rate of 600 to 3400 will feed satisfactory results, the flow rate being the volume of gas represents that passes through the apparatus per hour and per volume of catalyst, and wherein the volume of the gases is measured at normal temperature and normal pressure.

After the reaction in the catalytic zone has ended, the current the reaction vapors are passed through washing towers, whereby the vapors of the not converted alkylpyridine and the excess ammonia separated and again in the proceedings can be traced back. The CN-substituted pyridine derivatives can then be separated from the by-products and purified by the usual methods be e.g. B. by distillation or recrystallization.

In order to explain the method according to the invention, the following some preferred embodiments are given, including the method of manufacture of the catalyst is described. The amounts given in the examples are Weight quantities. Example z 3-picoline contained in a suitable container is evaporated by pumping heated air, and the resulting vapors are mixed with additional air, for which about 12 parts of air are required, mixed with about 8 parts ammonia, all calculated to z part picoline. the resulting vapor mixture is then heated to 300 ° and over a ferric vanadate catalyst, contained in a stainless steel pipe at a throughput rate of about 220o, the reaction chamber during the reaction on a Temperature is kept from 30o to 3z0 °. The vapors that make up the reaction zone have left, then go through an externally cooled separator, in which Most of the reaction products are collected in crystal form, and then passed through a washing tower containing cold water. The reaction product is thereupon by Dissolve and extract with a solvent and collected by distillation cleaned. The main product of the reaction is 3-cyanopyridine, which is obtained by the Boiling point, melting point and easy hydrolysability to nicotinic acid identified.

The catalyst used in the above procedure is made by dissolving of 40 g ferric chloride in zoo cm3 of distilled water and adding the solution to a hot solution of 56 g of ammonium vanadate in 1400 cm3 of distilled water. The yellow precipitate that forms changes its color after a short time in chocolate brown. This precipitate is then collected on a filter with Washed with water and dried in an oven at 125-135 °. The dried one Material is then ground into a coarse powder, the particles from zo to zo mesh screen size are separated and filled into a stainless steel tube, as in the above procedure Has found use. Example 2 A vapor mixture consisting of i part 3-picoline, ix parts air and 3.5 parts ammonia, will be at a throughput speed from 2300 passed through a reaction chamber containing a catalyst, obtained by suspending activated aluminum oxide in a solution of ferric nitrate, Drying and calcining the precipitate is available. The temperature in the The reaction zone is maintained at approximately 340 ° during the reaction. The reaction product is collected and purified as in example i. It consists of 3-cyanopyridine.

Example 3 A vapor mixture consisting of 1 part 3-picoline, 10 parts Air and 5 parts of ammonia are passed through at a throughput rate of 26oo a reaction chamber, which has a nickel catalyst on pumice stone support by impregnating pieces of pumice stone with molten nickel nitrate and subsequently calcining the thus treated pumice stone. The temperature during the reaction is about 35o °. The reaction product is collected and purified as in example i. It represents 3-cyanopyridine.

Example 4 A vapor mixture consisting of 1 part 3-picoline, 10 parts Air and 3 parts of ammonia are allowed to flow at a rate of 23oo flow through a chromium oxide catalyst on aluminum oxide support, which through Suspending commercially available activated aluminum oxide in an aqueous solution obtained from ammonium dichromate and calcining the thus treated alumina has been. The temperature during the reaction is 34o °. The reaction product obtained represents 3-cyanopyridine. Contains vanadium pentoxide catalyst on an alumina support. The temperature during the reaction is about 31o °. The reaction product obtained represents 3-cyanopyridine.

Example 8 A vapor mixture consisting of i part 6-methyl-3-ethylpyridine, q.2 parts air and ig parts ammonia, is made at one flow rate of 27oo passed through a reaction chamber which contains a ferric vanadate catalyst contains, which has been prepared according to Example 1. The temperature during the Response is about 36o. The reaction product obtained is 3-cyanopyridine . Example g A vapor mixture consisting of i part 6-methyl-3-ethylpyridine, 23 parts of air and 4 parts of ammonia are used at a flow rate of i7oo passed through a reaction chamber containing a vanadium pentoxide catalyst contains on aluminum oxide carrier. - The temperature during the reaction is about 36o °. The product obtained is 3-cyanopyridine.

Example 10 A vapor mixture consisting of 1 part 4-picoline, 10 parts air and 7.5 parts ammonia is passed at a throughput rate of 2300 through a reaction chamber which contains a vanadium pentoxide catalyst on an aluminum oxide carrier. The temperature during the reaction is about 300 °. The resulting reaction product is 4-cyanopyridine. The determination of the melting point of the mixture of the product and a sample of pure 4-cyanopyridine does not show any depression of the melting point. EXAMPLE 5 A vapor mixture consisting of 1 part 3-picoline, 10 parts air and 8.5 parts ammonia is passed at a throughput rate of 2700 through a reaction chamber which contains a vanadium pentoxide catalyst on an alumina support. The temperature during the reaction is approximately 300 °. The reaction product obtained is 3-cyanopyridine. EXAMPLE 6 A vapor mixture consisting of 1 part 3-picoline, 2 parts air and 7 parts ammonia is passed through a reaction chamber which contains a molybdenum oxide catalyst on an aluminum oxide carrier. The temperature during the reaction is 300 °. The reaction product obtained is 3-cyanopyridine. EXAMPLE 7 A vapor mixture consisting of 1 part 3-ethylpyridine, 24 parts air and 18 parts ammonia is passed through a reaction chamber at a throughput rate of 3400 which is an example ii a vapor mixture from i part 2-picoline, 8.5 parts air and 5.5 parts. Ammonia is passed through a reaction chamber containing an alumina-supported vanadium pentoxide catalyst at a rate of 23000. The temperature during the reaction is about 300 °. The reaction product is distilled under a vacuum of 12 mm and the fraction which distills at 12 to 14o ° is collected separately. It is recrystallized from a petroleum ether-gasoline mixture. The melting point of the recrystallized product is 107 °. The reaction product obtained is pyridine-2-carboxamide. The determination of the melting point of the mixture of the product and a sample of pure pyridine-2-carboxamide does not show any depression of the melting point.

Example 12 A vapor mixture consisting of i part 2, 6-lutidine (2, 6-dimethylpyridine), 22 parts of air and 15 parts of ammonia, is made at one flow rate of 23oo passed through a reaction chamber containing a vanadium pentoxide catalyst contains on aluminum oxide carrier. The raw one Product is under vacuum fractionated, and in this case throw two products separated and by recrystallization cleaned. The white product isolated first is identified as 2-cyano-6-methylpyriin. Its melting point is 72 to 74 °. Determination of the melting point of the mixture with a sample of pure product shows no melting point depression. The second product is 2-cyanopyridine-6-carboxylic acid ami 3 uni is also white in color. Its melting point lies at 184 to i87 °. The product delivers dipicolinic acid through alkali hydrolysis. Example 13 A vapor mixture consisting of 1 part 6-methyl-3-ethylpyridine, 25 parts Air and ii parts of ammonia, throw through at a throughput rate of 27oo passed a reaction chamber containing a Ferrivanaaatkatalysator. The temperature during the reaction is about 300 °. The reaction product is made by dissolving collected in a solvent. After distilling off the solvent, the Residue sublimed under vacuum and crystallized from methanol. The won The reaction product is 6-cyanopyridine-3-carboxylic acid amii c ar and has a melting point from 275 to 277 °. The determination of the melting point of the mixture of the product obtained with a synthetic sample does not show any depression of the melting point. Example 14 A vapor mixture consisting of 1 part 6-methyl-3-äthylpyrilin, 2o parts air and 4 parts ammonia, at a throughput rate of: zooo through a Reaction chamber passed, which contains a silver vanadate catalyst. The temperature during the reaction is about 35o °. The reaction product obtained provides 6-cyanopyridine-3-carboxamide.

The catalyst required here is produced in such a way that a solution of silver nitrate in distilled water to a solution of ammonium metavanadate allowed to act in distilled water in a ratio of i mole: i mole. The received Precipitate is collected on a filter, washed with distilled water and dried. After: grinding, the granules are 10 to 20 mesh screen size separated and placed in the reaction chamber. Example 15 A vapor mixture consisting of from i part of 6-methyl-3-äthylpyriiin, 16 parts of air and 4.5 parts of ammonia is passed through a reaction chamber at a throughput rate of 23oo, which contains a Ferriniob3.tkatalysator. The temperature during the reaction is 375 °. The reaction product obtained is 6-cyanopyri'in-3-carboxylic acid amii.

The catalyst is obtained by the action of 1 mole of ferric chloride in aqueous solution to 3 mol of potassium niobate in aqueous solution. The resulting precipitate is collected on a filter, washed with distilled water and dried. After cem: grinding, the granules of the 10 to 20 mesh sieve sizes are separated off and brought into the reaction chamber.

EXAMPLE 16 A vapor mixture consisting of one part 6-methyl-3-ethylpyridine, 28 parts air and 9.5 parts ammonia is passed at a space velocity of 160 ° C. through a reaction chamber which contains a vanadium pentoxide catalyst on an aluminum oxide carrier. The temperature during the reaction is 300 °. The reaction product obtained is 6-cyanopyriline-3-carboxamide.

The reaction mechanism of the present process is not final clarified, but it seems certain that the nitrogen of the ammonia in each case is bound to the carbon atom of an alkyl chain, which is attached to the pyrene ring, where instead of the mentioned alkyl group either a nitrile group or a Carboxamide group is formed. Since in all cases the reaction is water arises, it is evident that the oxygen in the air blends with that which has been released Hydrogen of the alkyl group and ammonia connects. When the alkyl group is 2 or contains several carbon atoms, carbon dioxide is also formed. this shows suggests that the oxygen in the air also interacts with all the carbon atoms in the chain of the alkyl radical or radicals but one connects.

Claims (6)

PATENT CLAIMS; i. Process for the production of pyridine derivatives, the one or more optionally further substituted CN radicals as core substituents contain, especially of cyanopyridines, pyrilincarboxamides or cyanpyridincarboxamides, characterized in that a vapor mixture of alkylpyriiins, ammonia and uni an oxygen-containing gas in which ammonia and oxygen expediently in the Excess are, at temperatures of 25 to 400 °, preferably 300 to 375 °, over conducts a catalyst containing an oxide or a salt of an element of the 5th, 6th or B. Group of the Periodic Table or a mixture thereof, preferably vanadium oxide or pentoxide, molybdenum oxyi, ferric vanadate or niobate or silver vanadate, the on a carrier, e.g. B. aluminum oxide, may be deposited, contains and the process products are isolated from the reaction mixture in a customary manner. 2. The method according to claim i, characterized in that one for the production of 3- or 4-Cyanpyridinen 3- or 4-Alkylpyri'ine used as starting material. 3. The method according to claim i, characterized in that one for the production of 6-substituted 2-Cyanpyrilinen 2, 6-Dialkylpyri'ine used as starting material uni maintains a reaction temperature of 300 to 32o °. 4. The method according to claim i, characterized in that one for the preparation of Pyriain- 2-carboxamide 2-alkylpyridines used as starting material and a reaction temperature of 300 to 320 ° stops. 5. The method according to claim z, characterized in that to produce 6-cyanopyridine-3-carboxamide 3, 6-dialkylpyridines as Starting material used and a reaction temperature of 3oo to 375 ° holds. 6. The method according to claim r, characterized in that one for the production of 2-cyanopyridine-6-carboxamide 2, 6-dialkylpyridines used as starting material.